Methods for making implantable medical devices

ABSTRACT

A coated implantable medical device  10  includes a structure  12  adapted for introduction into the vascular system, esophagus, trachea, colon, biliary tract, or urinary tract; at least one coating layer  16  posited on one surface of the structure; and at least one layer  18  of a bioactive material posited on at least a portion of the coating layer  16,  wherein the coating layer  16  provides for the controlled release of the bioactive material from the coating layer. In addition, at least one porous layer  20  can be posited over the bioactive material layer  18,  wherein the porous layer includes a polymer and provides for the controlled release of the bioactive material therethrough. Preferably, the structure  12  is a coronary stent. The porous layer  20  includes a polymer applied preferably by vapor or plasma deposition and provides for a controlled release of the bioactive material. It is particularly preferred that the polymer is a polyamide, parylene or a parylene derivative, which is deposited without solvents, heat or catalysts, and merely by condensation of a monomer vapor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.10/218,305, filed Aug. 14, 2002 now U.S. Pat. No. 7,550,005, which is acontinuation-in-part of application Ser. No. 09/027,054, filed Feb. 20,1998, now U.S. Pat. No. 6,774,278, issued Aug. 10, 2004, which claimedpriority to provisional application Ser. No. 60/038,459, filed Feb. 20,1997, and which was also a continuation-in-part application of andclaimed priority to application Ser. No. 08/645,646, filed May 16, 1996,now U.S. Pat. No. 6,096,070, issued Aug. 1, 2000, each of which ishereby incorporated by reference.

TECHNICAL FIELD

This invention relates generally to human and veterinary medicaldevices, and more particularly to devices incorporating drugs orbioactive agents.

BACKGROUND OF THE INVENTION

It has become common to treat a variety of medical conditions byintroducing an implantable medical device partly or completely into theesophagus, trachea, colon, biliary tract, urinary tract, vascular systemor other location within a human or veterinary patient. For example,many treatments of the vascular system entail the introduction of adevice such as a stent, a catheter, a balloon, a wire guide, a cannula,or the like. However, when such a device is introduced into andmanipulated through the vascular system, the blood vessel walls can bedisturbed or injured. Clot formation or thrombosis often results at theinjured site, causing stenosis or occlusion of the blood vessel.Moreover, if the medical device is left within the patient for anextended period of time, thrombus often forms on the device itself,again causing stenosis or occlusion. As a result, the patient is placedat risk of a variety of complications, including heart attack, pulmonaryembolism, and stroke. Thus, the use of such a medical device can entailthe risk of precisely the problems that its use was intended toameliorate.

Another way in which blood vessels undergo stenosis is through disease.Probably the most common disease causing stenosis of blood vessels isatherosclerosis. Atherosclerosis is a condition which commonly affectsthe coronary arteries, the aorta, the iliofemoral arteries and thecarotid arteries. Atherosclerotic plaques of lipids, fibroblasts, andfibrin proliferate and cause obstruction of an artery or arteries. Asthe obstruction increases, a critical level of stenosis is reached, tothe point where the flow of blood past the obstruction is insufficientto meet the metabolic needs of the tissue distal to (downstream of) theobstruction. The result is ischemia.

Many medical devices and therapeutic methods are known for the treatmentof atherosclerotic disease. One particularly useful therapy for certainatherosclerotic lesions is percutaneous transluminal angioplasty (PTA).During PTA, a balloon-tipped catheter is inserted in a patient's artery,the balloon being deflated. The tip of the catheter is advanced to thesite of the atherosclerotic plaque to be dilated. The balloon is placedwithin or across the stenotic segment of the artery, and then inflated.Inflation of the balloon “cracks” the atherosclerotic plaque and expandsthe vessel, thereby relieving the stenosis, at least in part.

While PTA presently enjoys wide use, it suffers from two major problems.First, the blood vessel may suffer acute occlusion immediately after orwithin the initial hours after the dilation procedure. Such occlusion isreferred to as “abrupt closure.” Abrupt closure occurs in perhaps fivepercent or so of the cases in which PTA is employed, and can result inmyocardial infarction and death if blood flow is not restored promptly.The primary mechanisms of abrupt closures are believed to be elasticrecoil, arterial dissection and/or thrombosis. It has been postulatedthat the delivery of an appropriate agent (such as an antithrombic)directly into the arterial wall at the time of angioplasty could reducethe incidence of thrombotic acute closure, but the results of attemptsto do so have been mixed.

A second major problem encountered in PTA is the re-narrowing of anartery after an initially successful angioplasty. This re-narrowing isreferred to as “restenosis” and typically occurs within the first sixmonths after angioplasty. Restenosis is believed to arise through theproliferation and migration of cellular components from the arterialwall, as well as through geometric changes in the arterial wall referredto as “remodeling” It has similarly been postulated that the delivery ofappropriate agents directly into the arterial wall could interrupt thecellular and/or remodeling events leading to restenosis. However, likethe attempts to prevent thrombotic acute closure, the results ofattempts to prevent restenosis in this manner have been mixed.

Non-atherosclerotic vascular stenosis may also be treated by PTA. Forexample, Takayasu arteritis or neurofibromatosis may cause stenosis byfibrotic thickening of the arterial wall. Restenosis of these lesionsoccurs at a high rate following angioplasty, however, due to thefibrotic nature of the diseases. Medical therapies to treat or obviatethem have been similarly disappointing.

A device such as an intravascular stent can be a useful adjunct to PTA,particularly in the case of either acute or threatened closure afterangioplasty. The stent is placed in the dilated segment of the artery tomechanically prevent abrupt closure and restenosis. Unfortunately, evenwhen the implantation of the stent is accompanied by aggressive andprecise antiplatelet and anticoagulation therapy (typically by systemicadministration), the incidence of thrombotic vessel closure or otherthrombotic complication remains significant, and the prevention ofrestenosis is not as successful as desired. Furthermore, an undesirableside effect of the systemic antiplatelet and anticoagulation therapy isan increased incidence of bleeding complications, most often at thepercutaneous entry site.

Other conditions and diseases are treatable with stents, catheters,cannulae and other devices inserted into the esophagus, trachea, colon,biliary tract, urinary tract and other locations in the body, or withorthopedic devices, implants, or replacements. It would be desirable todevelop devices and methods for reliably delivering suitable agents,drugs or bioactive materials directly into a body portion during orfollowing a medical procedure, so as to treat or prevent such conditionsand diseases, for example, to prevent abrupt closure and/or restenosisof a body portion such as a passage, lumen or blood vessel. As aparticular example, it would be desirable to have devices and methodswhich can deliver an antithrombic or other medication to the region of ablood vessel which has been treated by PTA, or by another interventionaltechnique such as atherectomy, laser ablation, or the like. It wouldalso be desirable that such devices would deliver their agents over boththe short term (that is, the initial hours and days after treatment) andthe long term (the weeks and months after treatment). It would also bedesirable to provide precise control over the delivery rate for theagents, drugs or bioactive materials, and to limit systemic exposure tothem. This would be particularly advantageous in therapies involving thedelivery of a chemotherapeutic agent to a particular organ or sitethrough an intravenous catheter (which itself has the advantage ofreducing the amount of agent needed for successful treatment), bypreventing stenosis both along the catheter and at the catheter tip. Awide variety of other therapies could be similarly improved. Of course,it would also be desirable to avoid degradation of the agent, drug orbioactive material during its incorporation on or into any such device.

SUMMARY OF THE INVENTION

The foregoing problems are solved and a technical advance is achieved inan illustrative vascular stent or other implantable medical device thatprovides a controlled release of an agent, drug or bioactive materialinto the vascular or other system, or other location in the body, inwhich a stent or other device is positioned. Applicants have discoveredthat the degradation of an agent, a drug or a bioactive material that isapplied to such a device can be avoided by positing a coating layer onone surface of the device structure. The agent, drug or bioactivematerial is posited over at least a portion of the coating layer,wherein the coating layer provides for a controlled release of thebioactive material posited thereon. Furthermore, the medical devicefurther includes a porous layer positioned over the bioactive materialwherein the porous layer is composed of a polymer and the polymerprovides for a controlled release of the bioactive material through theporous layer.

In one aspect, the coating layer comprises a non-porous material of forexample a parylene derivative. This coating layer has a thicknesspreferably in a range from 50 to 500,000 Angstroms, more preferably in arange from 100,000 to 500,000 Angstroms, and illustrativelyapproximately 200,000 Angstroms. In another aspect, the non-porousmaterial is either an adsorbent or an absorbent material, where thecoating layer of the adsorbent material has a thickness of approximately230,000 Angstroms. In another aspect of the invention, the bioactivematerial layer includes a chimeric monoclonal antibody such as anantiplatelet GP IIb/IIIa antibody.

In still another aspect of the invention, an adhesive promotion layer isposited on one surface of the structure on which the coating layer isposited over at least a portion thereof. Preferably the adhesionpromotion layer includes silane having a thickness in range of 0.5 to5,000 Angstroms.

Applicants have also discovered that the degradation of an agent, a drugor a bioactive material applied to such a device may be avoided bycovering the agent, drug or bioactive material with a porous layer of abiocompatible polymer that is applied without the use of solvents,catalysts, heat or other chemicals or techniques, which would otherwisebe likely to degrade or damage the agent, drug or material. Thosebiocompatible polymers may be applied preferably by vapor deposition orplasma deposition, and may polymerize and cure merely upon condensationfrom the vapor phase, or may be photolytically polymerizable and areexpected to be useful for this purpose. However, it should be recognizedthat other coating techniques may also be employed.

Preferably, when the device is intended for use in the vascular system,the bioactive material in the at least one layer is heparin or anotherantiplatelet or antithrombotic agent, or dexamethasone, dexamethasoneacetate, dexamethasone sodium phosphate, or another dexamethasonederivative or anti-inflammatory steroid. Furthermore, a wide range ofother bioactive materials can be employed, including, but not limitedto, the following categories of agents: thrombolytics, vasodilators,antihypertensive agents, antimicrobials or antibiotics, antimitotics,antiproliferatives, antisecretory agents, non-steroidalanti-inflammatory drugs, immunosuppressive agents, growth factors andgrowth factor antagonists, antitumor and/or chemotherapeutic agents,antipolymerases, antiviral agents, photodynamic therapy agents, antibodytargeted therapy agents, prodrugs, sex hormones, free radicalscavengers, antioxidants, biologic agents, radiotherapeutic agents,radiopaque agents and radiolabelled agents. The major restriction isthat the bioactive material must be able to withstand the coatingtechniques, for example, the vacuum employed during vapor deposition orplasma deposition of the at least one porous layer. In other words, thebioactive material must have a relatively low vapor pressure at thedeposition temperature, typically, near or at room temperature.

The at least one porous layer is preferably composed of a polyamide,parylene or a parylene derivative applied by catalyst-free vapordeposition and is conveniently about 5,000 to 250,000 Å thick, which isadequate to provide a controlled release of the bioactive material.“Parylene” is both a generic name for a known group of polymers based onp-xylylene and made by vapor phase polymerization, and a name for theunsubstituted form of the polymer; the latter usage is employed herein.More particularly, parylene or a parylene derivative is created by firstheating p-xylene or a suitable derivative at an appropriate temperature(for example, at about 950° C.) to produce the cyclic dimerdi-p-xylylene (or a derivative thereof). The resultant solid can beseparated in pure form, and then cracked and pyrolyzed at an appropriatetemperature (for example, at about 680° C.) to produce a monomer vaporof p-xylylene (or derivative); the monomer vapor is cooled to a suitabletemperature (for example, below 50° C.) and allowed to condense on thedesired object, for example, on the at least one layer of bioactivematerial. The resultant polymer has the repeating structure

CH₂C₆H₄CH₂

_(n), with n equal to about 5,000, and a molecular weight in the rangeof 500,000.

As indicated, parylene and parylene derivative coatings applicable byvapor deposition are known for a variety of biomedical uses, and arecommercially available from or through a variety of sources, includingSpecialty Coating Systems (100 Deposition Drive, Clear Lake, Wis.54005), Para Tech Coating, Inc. (35 Argonaut, Aliso Viejo, Calif. 92656)and Advanced Surface Technology, Inc. (9 Linnel Circle, Billerica, Mass.01821-3902).

The at least one porous layer can alternatively be applied by plasmadeposition. Plasma is an ionized gas maintained under vacuum and excitedby electrical energy, typically in the radiofrequency range. Because thegas is maintained under vacuum, the plasma deposition process occurs ator near room temperature. Plasma can be used to deposit polymers such aspoly(ethylene oxide), poly(ethylene glycol), and polypropylene oxide),as well as polymers of silicone, methane, tetrafluoroethylene (includingTEFLON brand polymers), tetramethyidisiloxane, and others.

While the foregoing represents some preferred embodiments of the presentinvention, other polymer systems may also be employed, e.g., polymersderived from photopolymerizeable monomers. Also, other coatingtechniques may be utilized, e.g., dipping, spraying, and the like.

The device may include two or more layers of different bioactivematerials atop the structure. However, for the purposes of the presentinvention, the same bioactive material will generally not be posited onthe different surfaces of the device within the same layer. In otherwords, each surface of the device structure will carry a differentbioactive material or materials except where the bioactive material isthe innermost or outermost layer, e.g. heparin may form the innermostlayer or the outermost layer or both. These additional layers may beplaced directly atop one another or can be separated by additionalporous polymer layers between each of them. Additionally, the layers ofbioactive materials can comprise a mixture of different bioactivematerials The porous layers are also preferably composed of parylene ora parylene derivative. Advantageously, the two or more bioactivematerials can have different solubilities, and the layer containing theless soluble bioactive material (for example, dexamethasone) ispreferably posited above the layer containing the more soluble bioactivematerial (for example, heparin). Unexpectedly, this has been found toincrease the in vitro release rate of some relatively less solublematerials such as dexamethasone, while simultaneously decreasing therelease rate of some relatively more soluble materials such as heparin.

While the structure included in the device may be configured in avariety of ways, the structure is preferably configured as a vascularstent composed of a biocompatible metal such as stainless steel, nickel,silver, platinum, gold, titanium, tantalum, iridium, tungsten, Nitinol,inconel, or the like. An additional substantially nonporous coatinglayer of parylene or a parylene derivative or other biocompatiblepolymer of about 50,000 to 500,000 Å thick may be posited directly atopthe vascular stent, beneath the at least one layer of bioactivematerial. The additional coating layer can merely be relatively lessporous than the at least one porous layer, but preferably issubstantially nonporous, that is, sufficiently nonporous to render thestent essentially impervious to blood during normal circumstances ofuse.

The device and methods of the present invention are useful in a widevariety of locations within a human or veterinary patient, such as inthe esophagus, trachea, colon, biliary tract, urinary tract and vascularsystem, as well as for subdural and orthopedic devices, implants orreplacements. They are particularly advantageous for reliably deliveringsuitable bioactive materials during or following an intravascularprocedure, and find particular use in preventing abrupt closure and/orrestenosis of a blood vessel. More particularly, they permit, forexample, the delivery of an antithrombotic, an antiplatelet, ananti-inflammatory steroid, or another medication to the region of ablood vessel which has been opened by PTA. Likewise, it allows for thedelivery of one bioactive material to, for example, the lumen of a bloodvessel and another bioactive material to the vessel wall. The use of aporous polymer layer permits the release rate of a bioactive material tobe carefully controlled over both the short and long terms.

These and other aspects of the present invention will be appreciated bythose skilled in the art upon the reading and understanding of thespecification.

In another aspect of the invention, the bioactive material is attachedto the non-porous layer and is advantageously eluted for prolongedperiods of time. The non-porous layer is attached to the base materialof the structure. The non-porous layer can be any of those previously orsubsequently listed herein, and, likewise, the bioactive material can beany of those previously or subsequently listed herein. Conveniently, andin a preferred embodiment, a glycoprotein IIb/IIIa inhibitor such ascommercially available ReoPro™ is attached to a non-porous layer ofparylene positioned on the outer surface of the medical device such as acoronary stent. The ReoPro™ is advantageously eluted from the surface ofthe stent for prolonged periods of time.

BRIEF DESCRIPTION OF THE DRAWING

A better understanding of the present invention will now be had uponreference to the following detailed description, when read inconjunction with the accompanying drawing, wherein like referencecharacters refer to like parts throughout the several views, and inwhich:

FIG. 1 is a cross-sectional view of a first preferred embodiment of thepresent invention;

FIG. 2 is a cross-sectional view of another preferred embodiment of thepresent invention;

FIG. 3 is a cross-sectional view of yet another preferred embodiment ofthe present invention;

FIG. 4 is a cross-sectional view of a further preferred embodiment ofthe present invention;

FIG. 5 is a cross-sectional view of an additional preferred embodimentof the present invention;

FIGS. 6A and 6B are cross-sectional views of an additional preferredembodiment of the present invention;

FIG. 7 is a partial plan view of an additional preferred embodiment ofthe present invention;

FIG. 8 is a partial, enlarged top view of FIG. 7;

FIG. 9 is an enlarged, sectional view along lines 9-9 of FIG. 8;

FIGS. 10A-10D are enlarged, partial cross-sectional views along lines10-10 of FIG. 8;

FIG. 11 depicts another aspect of the medical device of FIG. 1 utilizinga polymer coating layer with a bioactive material attached thereto; and

FIG. 12 depicts still another aspect of the medical device of FIG. 11 inwhich the polymer coating layer is-adhered to the outer surface of thedevice base material using an adhesive promotion layer.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

With reference now to FIG. 1, an implantable medical device 10 inaccordance with the present invention is shown and first comprises astructure 12 adapted for introduction into a human or veterinarypatient. “Adapted” means that the structure 12 is shaped and sized forsuch introduction. For clarity, only a portion of the structure 12 isshown in FIG. 1.

By way of example, the structure 12 is configured as a vascular stentparticularly adapted for insertion into the vascular system of thepatient. However, this stent structure can be used in other systems andsites such as the esophagus, trachea, colon, biliary ducts, urethra andureters, subdural among others. Indeed, the structure 12 canalternatively be configured as any conventional vascular or othermedical device, and can include any of a variety of conventional stentsor other adjuncts, such as helical wound strands, perforated cylinders,or the like. Moreover, because the problems addressed by the presentinvention arise with respect to those portions of the device actuallypositioned within the patient, the inserted structure 12 need not be anentire device, but can merely be that portion of a vascular or otherdevice which is intended to be introduced into the patient. Accordingly,the structure 12 can be configured as at least one of, or any portionof, a catheter, a wire guide, a cannula, a stent, a vascular or othergraft, a cardiac pacemaker lead or lead tip, a cardiac defibrillatorlead or lead tip, a heart valve, or an orthopedic device, appliance,implant, or replacement. The structure 12 can also be configured as acombination of portions of any of these.

Most preferably, however, the structure 12 is configured as a vascularstent such as the commercially available Gianturco-Roubin FLEX-STENT® orGR II™ coronary stent. from Cook-Incorporated, Bloomington, Ind. Suchstents are typically about 10 to about 60 mm in length and designed toexpand to a diameter of about 2 to about 6 mm when inserted into thevascular system of the patient. The Gianturco-Roubin stent in particularis typically about 12 to about 25 mm in length and designed to expand toa diameter of about 2 to about 4 mm when so inserted.

These stent dimensions are, of course, applicable to exemplary stentsemployed in the coronary arteries. Structures such as stents or catheterportions intended to be employed at other sites in the patient, such asin the aorta, esophagus, trachea, colon, biliary tract, or urinary tractwill have different dimensions more suited to such use. For example,aortic, esophageal, tracheal and colonic stents may have diameters up toabout 25 mm and lengths about 100 mm or longer.

The structure 12 is composed of a base material 14 suitable for theintended use of the structure 12. The base material 14 is preferablybiocompatible, although cytotoxic or other poisonous base materials maybe employed if they are adequately isolated from the patient. Suchincompatible materials may be useful in, for example, radiationtreatments in which a radioactive material is positioned by catheter inor close to the specific tissues to be treated. Under mostcircumstances, however, the base material 14 of the structure 12 shouldbe biocompatible.

A variety of conventional materials can be employed as the base material14. Some materials may be more useful for structures other than thecoronary stent exemplifying the structure 12. The base material 14 maybe either elastic or inelastic, depending upon the flexibility orelasticity of the polymer layers to be applied over it. The basematerial may be either biodegradable or non-biodegradable, and a varietyof biodegradable polymers are known. Moreover, some biologic agents havesufficient strength to serve as the base material 14 of some usefulstructures 12, even if not especially useful in the exemplary coronarystent.

Accordingly, the base material 14 can include at least one of stainlesssteel, tantalum, titanium, nitinol, gold, platinum, inconel, iridium,silver, tungsten, or another biocompatible metal, or alloys of any ofthese; carbon or carbon fiber; cellulose acetate, cellulose nitrate,silicone, polyethylene teraphthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible polymeric material, ormixtures or copolymers of these; polylactic acid, polyglycolic acid orcopolymers thereof, a polyanhydride, polycaprolactone,polyhydroxybutyrate valerate or another biodegradable polymer, ormixtures or copolymers of these; a protein, an extracellular matrixcomponent, collagen, fibrin or another biologic agent; or a suitablemixture of any of these. Stainless steel is particularly useful as thebase material 14 when the structure 12 is configured as a vascularstent.

Of course, when the structure 12 is composed of a radiolucent materialsuch as polypropylene, polyethylene, or others above, a conventionalradiopaque coating may and preferably should be applied to it. Theradiopaque coating provides a means for identifying the location of thestructure 12 by X-ray or fluoroscopy during or after its introductioninto the patient's vascular system.

With continued reference to FIG. 1, the vascular device 10 of thepresent invention next comprises at least one layer 18 of a bioactivematerial posited on one surface of the structure 12. For the purposes ofthe present invention, at least one bioactive material is posited on onesurface of the structure 12, and the other surface will either containno bioactive material or one or more different bioactive materials. Inthis manner, one or more bioactive materials or drugs may be delivered,for example, with a vascular stent, to the blood stream from the lumensurface of the stent, and a different treatment may be delivered on thevessel surface of the stent. A vast range of drugs, medicaments andmaterials may be employed as the bioactive material in the layer 18, solong as the selected material can survive exposure to the vacuum drawnduring vapor deposition or plasma deposition. Particularly useful in thepractice of the present invention are materials which prevent orameliorate abrupt closure and restenosis of blood vessels previouslyopened by stenting surgery or other procedures. Thrombolytics (whichdissolve, break up or disperse thrombi) and antithrombogenics (whichinterfere with or prevent the formation of thrombi) are especiallyuseful bioactive materials when the structure 12 is a vascular stent.Particularly preferred thrombolytics are urokinase, streptokinase, andthe tissue plasminogen activators. Particularly preferredantithrombogenics are heparin, hirudin, and the antiplatelets.

Urokinase is a plasminogen activating enzyme typically obtained fromhuman kidney cell cultures. Urokinase catalyzes the conversion ofplasminogen into the fibrinolytic plasmin, which breaks down fibrinthrombi.

Heparin is a mucopolysaccharide anticoagulant typically obtained fromporcine intestinal mucosa or bovine lung. Heparin acts as a thrombininhibitor by greatly enhancing the effects of the blood's endogenousantithrombin III. Thrombin, a potent enzyme in the coagulation cascade,is key in catalyzing the formation of fibrin. Therefore, by inhibitingthrombin, heparin inhibits the formation of fibrin thrombi.Alternatively, heparin may be covalently bound to the outer layer ofstructure 12. Thus, heparin would form the outermost layer of structure12 and would not be readily degraded enzymatically, and would remainactive as a thrombin inhibitor.

Of course, bioactive materials having other functions can also besuccessfully delivered by the device 10 of the present invention. Forexample, an antiproliferative agent such as methotrexate will inhibitover-proliferation of smooth muscle cells and thus inhibit restenosis ofthe dilated segment of the blood vessel. The antiproliferative isdesirably supplied for this purpose over a period of about four to sixmonths. Additionally, localized delivery of an antiproliferative agentis also useful for the treatment of a variety of malignant conditionscharacterized by highly vascular growth. In such cases, the device 10 ofthe present invention could be placed in the arterial supply of thetumor to provide a means of delivering a relatively high dose of theantiproliferative agent directly to the tumor.

A vasodilator such as a calcium channel blocker or a nitrate willsuppress vasospasm, which is common following angioplasty procedures.Vasospasm occurs as a response to injury of a blood vessel, and thetendency toward vasospasm decreases as the vessel heals. Accordingly,the vasodilator is desirably supplied over a period of about two tothree weeks. Of course, trauma from angioplasty is not the only vesselinjury which can cause vasospasm, and the device 10 may be introducedinto vessels other than the coronary arteries, such as the aorta,carotid arteries, renal arteries, iliac arteries or peripheral arteriesfor the prevention of vasospasm in them.

A variety of other bioactive materials are particularly suitable for usewhen the structure 12 is configured as something other than a coronarystent. For example, an anti-cancer chemotherapeutic agent can bedelivered by the device 10 to a localized tumor. More particularly, thedevice 10 can be placed in an artery supplying blood to the tumor orelsewhere to deliver a relatively high and prolonged dose of the agentdirectly to the tumor, while limiting systemic exposure and toxicity.The agent may be a curative, a pre-operative debulker reducing the sizeof the tumor, or a palliative which eases the symptoms of the disease.It should be noted that the bioactive material in the present inventionis delivered across the device 10, and not by passage from an outsidesource through any lumen defined in the device 10, such as through acatheter employed for conventional chemotherapy. The bioactive materialof the present invention may, of course, be released from the device 10into any lumen defined in the device, or to tissue in contact with thedevice and that the lumen may carry some other agent to be deliveredthrough it. For example, tamoxifen citrate, Taxol® or derivativesthereof Proscar®, Hytrin®, or Eulexin® may be applied to thetissue-exposed surface of the device for delivery to a tumor located,for example, in breast tissue or the prostate.

Dopamine or a dopamine agonist such as bromocriptine mesylate orpergolide mesylate is useful for the treatment of neurological disorderssuch as Parkinson's disease. The device 10 could be placed in thevascular supply of the thalamic substantia nigra for this purpose, orelsewhere, localizing treatment in the thalamus.

A wide range of other bioactive materials can be delivered by the device10. Accordingly, it is preferred that the bioactive material containedin the layer 18 includes at least one of heparin, covalent heparin, oranother thrombin inhibitor, hirudin, hirulog, argatroban,D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or anotherantithrombogenic agent, or mixtures thereof; urokinase, streptokinase, atissue plasminogen activator, or another thrombolytic agent, or mixturesthereof; a fibrinolytic agent; a vasospasm inhibitor; a calcium channelblocker, a nitrate, nitric oxide, a nitric oxide promoter or anothervasodilator; Hytrin® or other antihypertensive agents; an antimicrobialagent or antibiotic; aspirin, ticlopidine, a glycoprotein IIb/IIIainhibitor or another inhibitor of surface glycoprotein receptors, oranother antiplatelet agent; colchicine or another antimitotic, oranother microtubule inhibitor, dimethyl sulfoxide (DMSO), a retinoid oranother antisecretory agent; cytochalasin or another actin inhibitor; ora remodelling inhibitor; deoxyribonucleic acid, an antisense nucleotideor another agent for molecular genetic intervention; methotrexate oranother antimetabolite or antiproliferative agent; tamoxifen citrate,Taxol® or the derivatives thereof, or other anti-cancer chemotherapeuticagents; dexamethasone, dexamethasone sodium phosphate, dexamethasoneacetate or another dexamethasone derivative, or anotheranti-inflammatory steroid or non-steroidal antiinflammatory agent;cyclosporin or another immunosuppressive agent; trapidal (a PDGFantagonist), angiopeptin (a growth hormone antagonist), angiogenin, agrowth factor or an anti-growth factor antibody, or another growthfactor antagonist; dopamine, bromocriptine mesylate, pergolide mesylateor another dopamine agonist; ⁶⁰Co (5.3 year half life), ¹⁹²Ir (73.8days), ³²P (14.3 days), ¹¹¹In (68 hours), ⁹⁰Y (64 hours), ^(99m)Tc (6hours) or another radiotherapeutic agent; iodine-containing compounds,barium-containing compounds, gold, tantalum, platinum, tungsten oranother heavy metal functioning as a radiopaque agent; a peptide, aprotein, an enzyme, an extracellular matrix component, a cellularcomponent or another biologic agent; captopril, enalapril or anotherangiotensin converting enzyme (ACE) inhibitor; ascorbic acid, alphatocopherol, superoxide dismutase, deferoxamine, a 21-aminosteroid(lasaroid) or another free radical scavenger, iron chelator orantioxidant; a ¹⁴C-, ³H-, ¹³¹I-, ³²P- or ³⁶S-radiolabelled form or otherradiolabelled form of any of the foregoing; estrogen or another sexhormone; AZT or other antipolymerases; acyclovir, famciclovir,rimantadine hydrochloride, ganciclovir sodium, Norvir, Crixivan, orother antiviral agents; 5-aminolevulinic acid,meta-tetrahydroxyphenylchlorin, hexadecafluoro zinc phthalocyanine,tetramethyl hematoporphyrin, rhodamine 123 or other photodynamic therapyagents; an IgG2 Kappa antibody against Pseudomonas aeruginosa exotoxin Aand reactive with A431 epidermoid carcinoma cells, monoclonal antibodyagainst the noradrenergic enzyme dopamine beta-hydroxylase conjugated tosaporin or other antibody targeted therapy agents; gene therapy agents;and enalapril and other prodrugs; Proscar®, Hytrin® or other agents fortreating benign prostatic hyperplasia (BHP) or a mixture of any ofthese; and various forms of small intestine submucosa (SIS).

In a particularly preferred aspect, the layer of bioactive materialcontains preferably from about 0.01 mg to about 10 mg and morepreferably from about 0.1 mg to about 4 mg of the bioactive material percm² of the gross surface area of the structure. “Gross surface area”refers to the area calculated from the gross or overall extent of thestructure, and not necessarily to the actual surface area of theparticular shape or individual parts of the structure. In other terms,about 100 μg to about 300 μg of drug per 0.001 inch of coating thicknessmay be contained on the device surface.

When the structure 12 is configured as a vascular stent, however,particularly preferred materials for the bioactive material of the layer18 are heparin, anti-inflammatory steroids including but not limited todexamethasone and its derivatives, and mixtures of heparin and suchsteroids.

Still with reference to FIG. 1, the device 10 of the present inventionalso comprises at least one porous layer 20 posited over the layer 18 ofbioactive material and the bioactive-material-free surface. The purposeof the porous layer 20 is to provide a controlled release of thebioactive material when the device 10 is positioned in the vascularsystem of a patient. The thickness of the porous layer 20 is chosen soas to provide such control.

More particularly, the porous layer 20 is composed of a polymerdeposited on the bioactive material layer 18, preferably by vapordeposition. Plasma deposition may also be useful for this purpose.Preferably, the layer 20 is one that is polymerized from a vapor whichis free of any solvent, catalysts or similar polymerization promoters.Also preferably, the polymer in the porous layer 20 is one whichautomatically polymerizes upon condensation from the vapor phase,without the action of any curative agent or activity such as heating,the application of visible or ultraviolet light, radiation, ultrasound,or the like. Most preferably, the polymer in the porous layer 20 ispolyimide, parylene or a parylene derivative.

When first deposited, the parylene or parylene derivative is thought toform a network resembling a fibrous mesh, with relatively large pores.As more is deposited, the porous layer 20 not only becomes thicker, butit is believed that parylene or parylene derivative is also deposited inthe previously formed pores, making the existing pores smaller. Carefuland precise control over the deposition of the parylene or parylenederivative therefore permits close control over the release rate ofmaterial from the at least one layer 18 of bioactive material. It is forthis reason that the bioactive material lies under the at least oneporous layer 20, rather than being dispersed within or throughout it.The porous layer 20, however, also protects the bioactive material layer18 during deployment of the device 10, for example, during insertion ofthe device 10 through a catheter and into the vascular system orelsewhere in the patient.

As shown in FIG. 1, the device 10 of the present invention can furthercomprise at least one additional coating layer 16 posited between thestructure 12 and the at least one layer 18 of bioactive material. Whilethe additional coating layer 16 can simply be a medical grade primer,the additional coating layer 16 is preferably composed of the samepolymer as the at least one porous layer 20. However, the additionalcoating layer 16 is also preferably less porous than the at least oneporous layer 20, and is more preferably substantially nonporous.“Substantially nonporous” means that the additional coating layer 16 issufficiently impervious to prevent any appreciable interaction betweenthe base material 14 of the structure 12 and the blood to which thedevice 10 will be exposed during use. The use of an additional coatinglayer 16 which is substantially nonporous would permit the use of atoxic or poisonous base material 14, as mentioned above. Even if thebase material 14 of the structure 12 is biocompatible, however, it maybe advantageous to isolate it from the blood by use of a substantiallynonporous coating layer 16.

Other polymer systems that may find application within the scope of theinvention include polymers derived from photopolymerizable monomers suchas liquid monomers preferably having at least two cross linkable C—C(Carbon to Carbon) double bonds and being a non-gaseous additionpolymerizable ethylenically unsaturated compound, having a boiling pointabove 100° C., at atmospheric pressure, a molecular weight of about100-1500 and being capable of forming high molecular weight additionpolymers readily. More preferably, the monomer is preferably an additionphotopolymerizable polyethylenically unsaturated acrylic or methacrylicacid ester containing two or more acrylate or methacrylate groups permolecule or mixtures thereof. A few illustrative examples of suchmultifunctional acrylates are ethylene glycol diacrylate, ethyleneglycol dimethacrylate, trimethylopropane triacrylate, trimethylopropanetrimethacrylate, pentaerythritol tetraacrylate or pentaerythritoltetramethacrylate, 1,6-hexanediol dimethacrylate, and diethyleneglycoldimethacrylate.

Also useful in some special instances are monoacrylates such asn-butyl-acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate,lauryl-acrylate, and 2-hydroxy-propyl acrylate. Small quantities ofamides of (meth)acrylic acid such as N-methylol methacrylamide butylether are also suitable, N-vinyl compounds such as N-vinyl pyrrolidone,vinyl esters of aliphatic monocarboxylic acids such as vinyl oleate,vinyl ethers of diols such as butanediol-1, 4-divinyl ether and allylether and allyl ester are also suitable. Also included would be othermonomers such as the reaction products of di- or polyepoxides such asbutanediol-1, 4-diglycidyl ether or bisphenol A diglycidyl ether with(meth)acrylic acid. The characteristics of the photopolymerizable liquiddispersing medium can be modified for the specific purpose by a suitableselection of monomers or mixtures thereof.

Other useful polymer systems include a polymer that is biocompatible andminimizes irritation to the vessel wall when the stent is implanted. Thepolymer may be either a biostable or a bioabsorbable polymer dependingon the desired rate of release or the desired degree of polymerstability, but a bioabsorbable polymer is preferred for this embodimentsince, unlike a biostable polymer, it will not be present long afterimplantation to cause any adverse, chronic local response. Bioabsorbablepolymers that could be used include poly(L-lactic acid),polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), copoly(ether-esters) (e.g., PEO/PLA),polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid. Also,biostable polymers with a relatively low chronic tissue response such aspolyurethanes, silicones, and polyesters could be used and otherpolymers could also be used if they can be dissolved and cured orpolymerized on the stent such as polyolefins, polyisobutylene andethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinylhalide polymers and copolymers, such as polyvinyl chloride; polyvinylethers, such as polyvinyl methyl ether; polyvinylidene halides, such aspolyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile,polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinylesters, such as polyvinyl acetate; copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins, polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins, polyurethanes; rayon; rayon-triacetate; cellulose, celluloseacetate, cellulose butyrate; cellulose acetate butyrate; cellophane;cellulose nitrate; cellulose propionate; cellulose ethers; andcarboxymethyl cellulose.

While plasma deposition and vapor phase deposition may be a preferredmethod for applying the various coatings on the stent surfaces, othertechniques may be employed. For example, a polymer solution may beapplied to the stent and the solvent allowed to evaporate, therebyleaving on the stent surface a coating of the polymer and thetherapeutic substance. Typically, the solution can be applied to thestent by either spraying the solution onto the stent or immersing thestent in the solution. Whether one chooses application by immersion orapplication by spraying depends principally on the viscosity and surfacetension of the solution; however, it has been found that spraying in afine spray such as that available from an airbrush will provide acoating with the greatest uniformity and will provide the greatestcontrol over the amount of coating material to be applied to the stent.In either a coating applied by spraying or by immersion, multipleapplication steps are generally desirable to provide improved coatinguniformity and improved control over the amount of therapeutic substanceto be applied to the stent.

When the layer 18 of bioactive material contains a relatively solublematerial such as heparin, and when the at least one porous layer 20 iscomposed of parylene or a parylene derivative, the at least one porouslayer 20 is preferably about 5,000 to 250,000 Å thick, more preferablyabout 5,000 to 100,000 Å thick, and optimally about 50,000 Å thick. Whenthe at least one additional coating layer 16 is composed of paryiene ora parylene derivative, the at least one additional coating is preferablyabout, 50,000 to 500,000 Å thick, more preferably about 100,000 to500,000 Å thick, and optimally about 200,000 Å thick.

When the at least one layer 18 of bioactive material contains arelatively soluble material such as heparin, the at least one layer 18preferably contains a total of about 0.1 to 4 mg of bioactive materialper cm² of the gross surface area of the structure 12. This provides arelease rate for the heparin (measured in vitro) which is desirably inthe range of 0.1 to 0.5 mg/cm² per day, and preferably about 0.25 mg/cm²per day, under typical blood flows through vascular stents. It should benoted that the solubility of dexamethasone can be adjusted as desired,with or without the inclusion of heparin, by mixing it with one or moreof its relatively more soluble derivatives, such as dexamethasone sodiumphosphate.

FIG. 11 depicts another aspect of device 10 of the present invention inwhich coating layer 16 is applied directly to the outer surface of basematerial 14 of structure 12. In this configuration, coating layer 16 ispreferably a non-porous coating layer as previously described. Whencoating layer 16 comprises a parylene derivative, non-porous coatinglayer 16 ranges in thickness from 50,000 to 500,000 Å, more preferrablyin the range of 100,000 to 500,000 Å, and optimally about 200,000 Å. Inthis aspect of the invention, non-porous coating layer 16 is also anadsorbent in which an adsorbent is defined as an agent that attractsother materials or particles to its surface as indicated in Dorland'sIllustrated Medical Dictionary 26th Edition by W.B. Saunders Co.,Philadelphia, Pa. Bioactive material 18 is then attached to the surfaceof coating layer 16. An additional coating layer 20 can be applied overbioactive material layer 18. Alternatively, alternating layers ofcoating material and the same or different bioactive materials can beapplied to the surface of bioactive material layer 18. However, in thisparticular aspect of the invention, the outer layer of structure 12 is abioactive material layer 18.

In still another aspect of the present invention as depicted in FIG. 11,coating layer 16 can be considered an adsorbent layer and/or anabsorbent layer in which a bioactive material is attached thereto. Inone particular example, device 10 is a stainless steel GR II™ stent inwhich the stainless steel base material 14 of structure 12 is coatedwith a polymer and, in particular, parylene. This adsorbent polymerlayer 16 of parylene is approximately 230,000 Å thick. Bioactivematerial layer 18 of the antiplatelet GP IIb/IIIa antibody (AZ1) waspassively loaded on adsorbent polymer layer 16. The polymer coatedstainless steel stents were immersed for approximately 24 hours in abuffered aqueous solution of AZ1 antibody (1 mg/ml, pH=7.2) at 37° C.AZ1 is a monoclonal anti-rabbit platelet glycoprotein (GP) IIb/IIIaantibody. Using radio-labeled AZ1, it was demonstrated thatapproximately 0.02 μg antibody was loaded per mm² stent surface area(approximately 2 μg total for a 3×20 mm GR II™ stent). It was alsodemonstrated that in an in-vitro flow system (10 ml/min, 1% BSA in PBS)approximately half the loaded antibody remained on the stent afterapproximately 10 days perfusion.

The mechanism by which the stent is loaded with drug are thought toinclude adsorption onto the surface of the polymer layer and/orabsorption into the polymer.

Previous studies with similar loading and release of AZ1 from cellulosecoated stainless steel stents showed inhibition of platelet aggregationand reduced thrombosis rates in a rabbit model of deep arterial injury.(Aggarwal et al., Antithrombotic Potential of Polymer-Coated StentsEluting Platelet Glycoprotein IIb/IIIa Receptor Antibody, American HeartAssociation Circulation Vol. 94 No. 12, Dec. 15, 1996, pp 3311-3317).

In another example, c7E3 Fab as bioactive material layer 18 is attachedto polymer coating layer 16. Bioactive material c7E3 Fab is a chimericmonoclonal antibody that acts upon the Gp IIa/IIIb integrin on plateletsto inhibit their aggregation. This antibody or receptor blocker can beused in humans intravenously to prevent thrombosis during coronaryangioplasty. This receptor blocker is also known as ReoPro™ availablefrom Eli Lilly, Indianapolis, Ind. Bioactive material layer 18 of theantiplatelet GP IIb/IIIa antibody (c7E3 Fab) was passively loaded onadsorbent polymer layer 16. The polymer coated stainless steel stentswere immersed for approximately 24 hours in a buffered aqueous solutionof c7E3 Fab antibody (1 mg/ml, pH=7.2) at 37° C. c7E3 Fab is aninhibitor of platelet thrombus in humans. Using radio-labeled c7E3 Fab,it was demonstrated that approximately 0.010 μg antibody was loaded permm² stent surface area (approximately 10 μg total for a 3×20 mm GR II™stent). It was also demonstrated that in an in-vitro flow system (10ml/min, 1% BSA in PBS) approximately half the loaded antibody remainedon the stent after approximately 10 days perfusion. FIG. 12 depictsstill another aspect of device 10 of FIG. 11. In this embodiment, aparylene adhesion promotion layer 30 is first applied to stainless steelbase material 14 of structure 12. By way of example, adhesion promotionlayer 30 is a thin layer of silane having a thickness in the range of,for example, 0.5 to 5,000 Å and preferrably, 2 to 50 Å. This silanepromotion layer is preferrably A-174 silane including agamma-methacryloxypropyltrimethoxysilane, which is available fromSpecialty Coating Systems Inc., Indianapolis, Ind. In preparing theouter surface of base material 14, it is first cleaned with isopropylalcohol. The stent is then dipped in the silane to apply a very thinlayer thereof to the outer surface of the base material. Polymer coatinglayer 16 of parylene is then applied to the silane layer. Other methodsof preparing the outer surface of base material 14 include plasmaetching and grit blasting. Preparation includes cleaning the outersurface of the base material with isopropyl alcohol, plasma etching theouter surface of the base material and applying the silane to the plasmaetched surface. With grit blasting, the outer surface of the basematerial is grit blasted and then cleaned with isopropyl alcohol towhich silane is applied to the cleansed grit blasted surface.

As shown in FIG. 2, the device 10 of the present invention is notlimited to the inclusion of a single layer 18 of bioactive material. Thedevice 10 can, for example, comprise a second layer 22 of a bioactivematerial posited over the structure 12. The bioactive material of thesecond layer 22 can be, but need not necessarily be, different from thebioactive material of the first bioactive material layer 18, only thatthey not be posited on the same surface of the device 10 without theintermediate porous layer 24. The use of different materials in thelayers 18 and 22 allows the device 10 to perform more than a singletherapeutic function.

The device 10 of the present invention can further comprise anadditional porous layer 24 of the polymer posited between each of thelayers 18 and 22 of bioactive material. It is reiterated that bioactivematerial 18 is on one surface of structure 12. The other surface may befree of bioactive material or may comprise one or more differentbioactive materials. The additional porous layer 24 can give thebioactive materials in the layers 18 and 22 different release rates.Simultaneously, or alternatively, the device 10 may employ bioactivematerials in the two layers 18 and 22 which are different from oneanother and have different solubilities. In such a case, it isadvantageous and preferred to position the layer 22 containing the lesssoluble bioactive material above the layer 18 containing the moresoluble bioactive material, Alternatively, the bioactive material 18 maybe contained in holes, wells, slots and the like occurring within thestent surface as illustrated in FIGS. 8-10 and will further be discussedin greater detail.

For example, when the structure 12 of the device 10 is configured as avascular stent, it is advantageous for the at least one layer 18 tocontain relatively soluble heparin, and the second layer 22 to containrelatively less soluble dexamethasone. Unexpectedly, the heparinpromotes the release of the dexamethasone, increasing its release ratemany times over the release rate of dexamethasone in the absence ofheparin. The release rate of the heparin is also lowered, somewhat lessdramatically than the increase of the dexamethasone release rate. Moreparticularly, when dexamethasone is disposed by itself beneath a porousparylene layer 20 dimensioned as disclosed above, its release rate isnegligible; an adequate release rate is obtained only when the thicknessof the porous layer 20 is reduced by a factor of ten or more. Incontrast, when a layer 22 of dexamethasone is disposed over a layer 18of heparin, and beneath a porous parylene layer 20 dimensioned as above,the dexamethasone may be released at a desirable rate of about 1 to 10μg/cm² per day. Moreover, and even more unexpectedly, this increasedrelease rate for the dexamethasone is thought to be maintained evenafter all of the heparin has been released from the layer 18.

The bioactive material layers 18 and/or 22 are applied to the device 10independent of the application of the porous polymer layers 20 and/or24. Any mixing of a bioactive material from the layers 18 and/or 22 intothe porous layers 20 and/or 24, prior to introducing the device 10 intothe vascular system of the patient, is unintentional and merelyincidental. This gives significantly more control over the release rateof the bioactive material than the simple dispersal of a bioactivematerial in a polymeric layer.

The device 10 need not include the additional porous layer 24 when twoor more layers 18 and 22 of bioactive material are present. As shown inFIG. 3, the layers 18 and 22 do not have to be separated by a porouslayer, but can instead lie directly against one another. It is stilladvantageous in this embodiment to position the layer 22 containing therelatively less soluble bioactive material above the layer 18 containingthe relatively more soluble bioactive material.

Whether or not the additional porous layer 24 is present, it ispreferred that the layers 18 and 22 contain about 0.05 to 2.0 mg of eachof heparin and dexamethasone, respectively, per 1 cm² of the grosssurface area of the structure 12. The total amount of bioactive materialposited in the layers 18 and 22 over the structure 12 is thus preferablyin the range of about 0.1 to 10 mg/cm².

Some dexamethasone derivatives, such as dexamethasone sodium phosphate,are substantially more soluble than dexamethasone itself. If a moresoluble dexamethasone derivative is used as the bioactive material inthe device 10 of the present invention, the thickness of the at leastone porous layer 20 (and of the additional porous layer 24) should beadjusted accordingly.

The particular structure of the device 10 as disclosed may be adapted tospecific uses in a variety of ways. For example, the device 10 mayinclude further layers of the same or different bioactive materials.These additional layers of bioactive material may or may not beseparated by additional porous layers, as convenient or desired.Alternatively, additional porous layers may separate only some of theadditional layers of bioactive material. Moreover, one bioactivematerial may be placed on one portion of the structure 12 of the device10, and another bioactive material placed on a different portion of thestructure 12 of the device 10.

Alternatively, the device 10 need not include the additional coatinglayer 16 at all. Such a configuration is shown in FIG. 4, in which thebioactive material layer 18 is posited directly atop the base material14 of the structure 12. In such a case, it may be highly advantageous tosurface process or surface activate the base material 14, to promote thedeposition or adhesion of the bioactive material on the base material14, especially before the depositing of the at least one porous layer20. Surface processing and surface activation can also selectively alterthe release rate of the bioactive material. Such processing can also beused to promote the deposition or adhesion of the additional coatinglayer 16, if present, on the base material 14. The additional coatinglayer 16 itself, or any second or additional porous layer 24 itself, cansimilarly be processed to promote the deposition or adhesion of thebioactive material layer 18, or to further control the release rate ofthe bioactive material.

Useful methods of surface processing can include any of a variety ofsuch procedures, including: cleaning; physical modifications such asetching, drilling, cutting, or abrasion; and chemical modifications suchas solvent treatment, the application of primer coatings, theapplication of surfactants, plasma treatment, ion bombardment andcovalent bonding.

It has been found particularly advantageous to plasma treat theadditional coating layer 16 (for example, of paryiene) before depositingthe bioactive material layer 18 atop it. The plasma treatment improvesthe adhesion of the bioactive material, increases the amount ofbioactive material that can be deposited, and allows the bioactivematerial to be deposited in a more uniform layer. Indeed, it is verydifficult to deposit a hygroscopic agent such as heparin on anunmodified parylene surface, which is hydrophobic and poorly wettable.However, plasma treatment renders the parylene surface wettable,allowing heparin to be easily deposited on it.

Any of the porous polymer layers 20 and 24 may also be surface processedby any of the methods mentioned above to alter the release rate of thebioactive material or materials, and/or otherwise improve thebiocompatibility of the surface of the layers. For example, theapplication of an overcoat of polyethylene oxide, phosphatidylcholine ora covalently bound bioactive material, e.g., covalently attached heparinto the layers 20 and/or 24 could render the surface of the layers moreblood compatible. Similarly, the plasma treatment or application of ahydrogel coating to the layers 20 and/or 24 could alter their surfaceenergies, preferably providing surface energies in the range of 20 to 30dyne/cm, thereby rendering their surfaces more biocompatible.

Referring now to FIG. 5, an embodiment of the device 10 is there shownin which a mechanical bond or connector 26 is provided between (a) anyone of the porous layers 20 and 24, and (b) any or all of the other ofthe porous layers 20 and 24, the additional coating layer 16 and thebase material 14. The connector 26 reliably secures the layers 16, 20and/or 24 to each other, and or to the base material 14. The connector26 lends structural integrity to the device 10, particularly after thebioactive material layer or layers 18 and/or 20 have been fully releasedinto the patient.

For simplicity, the connector 26 is shown in FIG. 5 as a plurality ofprojections of the base material 14 securing a single porous layer 20 tothe base material 14. The connector 26 may alternatively extend from theporous layer 20, through the bioactive material layer 18, and to thebase material 14. In either case, a single layer 18 of bioactivematerial, divided into several segments by the connector 26, is positedbetween the porous layer 20 and the base material 14. The connectors canalso function to partition the different bioactive agents into differentregions of the device's surface.

The connector 26 may be provided in a variety of ways. For example, theconnector 26 can be formed as a single piece with the base material 14during its initial fabrication or molding into the structure 12. Theconnector 26 can instead be formed as a distinct element, such as abridge, strut, pin or stud added to an existing structure 12. Theconnector 26 can also be formed as a built-up land, shoulder, plateau,pod or pan on the base material 14. Alternatively, a portion of the basematerial 14 between the desired locations of plural connectors 26 may beremoved by etching, mechanical abrasion, or the like, and the bioactivematerial layer 18 deposited between them. The connector 26 can also beformed so as to extend downwards towards the base material 14, by wipingor etching away a portion of a previously applied bioactive materiallayer 18, and allowing the porous layer 20 to deposit by vapordeposition or plasma deposition directly on the bare portions of thebase material 14. Other ways to expose a portion of the base material 14to direct connection to the porous layer 20 will be evident to thoseskilled in this area.

In another preferred embodiment, as illustrated in FIGS. 6A, 6B and 7, abioactive material 18 is posited on the one surface of base material 14making up structure 12 in FIG. 6A. FIG. 7 shows a stent 10 in its flator planar state prior to being coiled and showing porous layer 20applied to its outermost surface. FIGS. 6A and 6B are section viewsalong line 6-6 of FIG. 7. The bioactive material 18 posited on the onesurface of base material 14 in FIG. 6A may be a number of differenttherapeutic and/or diagnostic agents. For example, the device 10 may bea stent which is placed in the body of a patient near a tumor to delivera chemotherapeutic agent, such as tamoxifen citrate or Taxol®, directlyto the tumor. A porous layer 20 is posited over the bioactive material18 to provide a smoother surface as well as a more controlled release ofthe bioactive material 18. As further illustrated in FIG. 6A, theopposite surface of the device may have, for example, heparin 18′covalently bonded to porous layer 20, particularly where this surfacefaces, for example, the lumen of a blood vessel, to provideantithrombotic effect and blood compatibility. It is pointed out, as hasbeen discussed herein, a third but different bioactive material may beposited (not shown) on the opposite surface of base material 14 from thefirst bioactive material 18 and on the same side of base material 14 asthe covalently bound heparin or any other bioactive material includingother covalently bound bioactive materials and separated by porous layer20.

A variation of the embodiment shown in FIG. 6A is illustrated in FIG.6B, where two bioactive materials 18 and 18′ are posited on the samesurface of base material 14 of structure 12. A porous layer 20 may bedeposited over the bioactive materials 18 and 18′ as well as thebioactive-material-free surface of based material 14. This embodimentillustrates a situation where it may be desirable to deliver two agentsto the tissue to which the particular surface of device 10 is exposed,e.g., an antiinflammatory agent and an antiviral agent. Moreover, theopposite surface of the device free of bioactive material is availablefor positing one or more bioactive materials or therapeutic agents,e.g., an antithrombotic agent.

As has been previously discussed, multiple layers of bioactive materialsand porous layers may be applied to the device 10 where the limitingfactors become the total thickness of the device, the adhesion ofmultiple layers and the like.

In still another embodiment of the present invention, the device of thepresent invention includes apertures within the device for containingthe bioactive material. This embodiment is illustrated in FIGS. 8, 9,10A, 10B, 10C and 10D. FIG. 8 shows an arm of the stent of FIG. 7wherein the arm includes holes 28 into which a bioactive material iscontained. FIG. 9 shows a section of the arm of the stent along lines9-9 of FIG. 8. Bioactive material 18 is contained within the hole 28where the base material 14 contains coating 16 and further where porouslayer 20 forms the outer most layer for the bioactive material 18 todiffuse through. In an alternative embodiment, wells 28′ may be cut,etched or stamped into the base material 14 of the device in which abioactive material 18 may be contained. This embodiment is illustratedin FIGS. 10A, 10B, 10C and 10D which are partial sectional FIGs. takenalong line 10-10 of FIG. 8 except wherein holes 28 in FIG. 8 are insteadwells 28′ in FIGS. 10A-10D. The wells 28′ may also be in the form ofslots or grooves in the surface of the base material 14 of the medicaldevice. This aspect of the invention provides the advantage of bettercontrolling the total amount of the bioactive material 18 to be releasedas well as the rate at which it is released. For example, a V-shape well28′, as illustrated in FIG. 10D, will contain less quantity of bioactivematerial 18 and release the material at geometric rate as compared to asquare shaped well 28′, as illustrated in FIG. 10B, which will have amore uniform, linear release rate.

The holes, wells, slots, grooves and the like, described above, may beformed in the surface of the device 10 by a variety of techniques. Forexample, such techniques include drilling or cutting by utilizinglasers, electron-beam machining and the like or employing photoresistprocedures and etching the desired apertures.

All the bioactive materials discussed above that may be coated on thesurface of the device 10 may be used to be contained within theapertures of this aspect of the invention. Likewise, layers of bioactivematerials and porous layers may be applied and built up on the exteriorsurfaces of the device as described previously with regard to otheraspects of the invention, e.g., heparin, may be covalently bound to onesurface of the device illustrated in FIG. 9.

The method of making the device 10 according to the present inventionmay now be understood. In its simplest form, the method comprises thesteps of depositing the at least one layer 18 of bioactive material overthe structure 12, followed by depositing the at least one porous layer20, preferably by vapor deposition or plasma deposition, over the atleast one bioactive material layer 18 on the one surface of structure12. The at least one porous layer 20 being composed of a biocompatiblepolymer and being of a thickness adequate to provide a controlledrelease of the bioactive material. Preferably, the at least oneadditional coating layer 16 is first posited by vapor depositiondirectly on the base material 14 of the structure 12. Such deposition iscarried out by preparing or obtaining di-p-xylylene or a derivativethereof, sublimating and cracking the di-p-xylylene. or derivative toyield monomeric p-xylylene or a monomeric derivative, and allowing themonomer to simultaneously condense on and polymerize over the basematerial 14. The deposition step is carried out under vacuum, and thebase material 14 maintained at or near room temperature during thedeposition step. The deposition is carried out in the absence of anysolvent or catalyst for the polymer, and in the absence of any otheraction to aid polymerization. One preferred derivative for carrying outthe deposition step is dichloro-di-p-xylylene. The parylene or parylenederivative is preferably applied at the thickness disclosed above, toyield a coating layer 16 which is substantially nonporous, but in anyevent less porous than the at least one porous layer 20 to be applied.If required by the composition of the coating layer 16, the layer 16 isthen surface processed in an appropriate manner, for example, by plasmatreatment as disclosed above.

The at least one layer 18 of the desired bioactive material or materialsis then applied to the one surface of the structure 12, and inparticular, onto the additional coating layer 16. This application stepcan be carried out in any of a variety of convenient ways, such as bydipping, rolling, brushing or spraying a fluid mixture of the bioactivematerial onto the additional coating layer 16, or by electrostaticdeposition of either a fluid mixture or dry powder of the bioactivematerial, or by any other appropriate method. Different bioactive agentsmay be applied to different sections or surfaces of the device.

It can be particularly convenient to apply a mixture of the bioactivematerial or materials and a volatile fluid over the structure, and thenremove the fluid in any suitable way, for example, by allowing it toevaporate. When heparin and/or dexamethasone or its derivatives serve asthe bioactive material(s), the fluid is preferably ethyl alcohol. Thebioactive material is preferably applied in an amount as disclosedabove.

Other methods of depositing the bioactive material layer 18 over thestructure 12 would be equally useful. Without regard to the method ofapplication, however, what is important is that the bioactive materialneed only be physically held in place until the porous layer 20 isdeposited over it. This can avoid the use of carriers, surfactants,chemical binding and other such methods often employed to hold abioactive agent on other devices. The additives used in such methods maybe toxic, or the additives or methods may alter or degrade the bioactiveagent, rendering it less effective, or even toxic itself. Nonetheless,if desired these other methods may also be employed to deposit thebioactive material layer 18 of the present invention.

The bioactive material may, of course, be deposited on the one surfaceof the structure 12 as a smooth film or as a layer of particles.Moreover, multiple but different bioactive materials may be deposited ina manner that different surfaces of the device contain the differentbioactive agents. In the latter case, the particle size may affect theproperties or characteristics of the device 10, such as the smoothnessof the uppermost porous coating 20, the profile of the device 10, thesurface area over which the bioactive material layer 18 is disposed, therelease rate of the bioactive material, the formation of bumps orirregularities in the bioactive material layer 18, the uniformity andstrength of adhesion of the bioactive material layer 18, and otherproperties or characteristics. For example, it has been useful to employmicronized bioactive materials, that is, materials which have beenprocessed to a small particle size, typically less than 10 μm indiameter. However, the bioactive material may also be deposited asmicroencapsulated particles, dispersed in liposomes, adsorbed onto orabsorbed into small carrier particles, or the like.

In still another embodiment according to the present invention, thebioactive material may be posited on the one surface of structure 12 ina specific geometric pattern. For example, the tips or arms of a stentmay be free of bioactive material, or the bioactive material may beapplied in parallel lines, particularly where two or more bioactivematerials are applied to the same surface.

In any event, once the bioactive material layer 18 is in place, the atleast one porous layer 20 is then applied over the at least onebioactive material layer 18 in the same manner as for the application ofthe at least one additional coating 16. A polymer such as parylene or aparylene derivative is applied at the lesser thickness disclosed above,however, so as to yield the at least one porous layer 20.

Any other layers, such as the second bioactive material layer 22 or theadditional porous layer 24, are applied in the appropriate order and inthe same manner as disclosed above. The steps of the method arepreferably carried out with any of the bioactive materials, structures,and base materials disclosed above.

Of course, polyimide may be deposited as any or all of the porous andadditional coating layers 20, 24 and/or 16 by vapor deposition in amanner similar to that disclosed above for parylene and its derivatives.Techniques for the plasma deposition of polymers such as poly(ethyleneoxide), poly(ethylene glycol), poly(propylene oxide), silicone, or apolymer of methane, tetrafluoroethylene or tetramethyl-disiloxane onother objects are well-known, and these techniques may be useful in thepractice of the present invention.

Another technique for controlling the release of the bioactive materialmay include depositing monodispersed polymeric particles, i.e., referredto as porogens, on the surface of the device 10 comprising one or morebioactive materials prior to deposition of porous layer 20. After theporous layer 20 is deposited and cured, the porogens may be dissolvedaway with the appropriate solvent, leaving a cavity or pore in the outercoating to facilitate the passage of the underlying bioactive materials.

The method of using the device 10 of the present invention in medicallytreating a human or veterinary patient can now be easily understood aswell. The method of the present invention is an improvement overprevious methods which include the step of inserting into a patient animplantable vascular device 10, the device 10 comprising a structure 12adapted for introduction into the vascular system of a patient, and thestructure 12 being composed of a base material 14. The method accordingto the present invention comprises the preliminary steps of depositingat least one layer 18 of a bioactive material on one surface of thestructure 12, followed by depositing at least one porous layer 20 overthe at least one bioactive material layer 18, the porous layer 20 beingcomposed of a polymer and having a thickness adequate to provide acontrolled release of the bioactive material when the device 10 ispositioned in the patient's vascular system.

The method can further entail carrying out the two depositing steps withthe various embodiments of the device 10 disclosed above, in accordancewith the method of making the device 10 disclosed above. Moreparticularly, the step of depositing the at least one porous layer 20can comprise polymerizing the at least one layer 20 from a monomervapor, preferably a vapor of parylene or a parylene derivative, free ofany solvent or catalyst. The method can also comprise the step ofdepositing the at least one additional coating layer 16 between thestructure 12 and the at least one bioactive material layer 18.

The method of treatment according to the present invention is completedby inserting the device 10 into the vascular system of the patient. Theat least one porous layer 20 and any additional porous layers 24automatically release the bioactive material or materials in acontrolled fashion into the patient.

The remaining details of the method of medical treatment are the same asthose disclosed with respect to the method of making the device 10 ofthe present invention; for the sake of brevity, they need not berepeated here.

In view of the disclosure above, it is clear that the present inventionprovides an implantable medical device which achieves precise controlover the release of one or more bioactive materials contained in thedevice. Moreover, the polyimide, parylene, parylene derivative or otherpolymeric layers 16, 20 and/or 24 can be remarkably thin, in comparisonto the thicknesses required for other polymer layers. The bulk orsubstantial majority of the overall coating on the structure 12 cantherefore consist of bioactive material. This allows the supply ofrelatively large quantities of bioactive material to the patient, muchgreater than the amounts supplied by prior devices. These quantities ofbioactive material can be supplied to any of a wide variety of locationswithin a patient during or after the performance of a medical procedure,but are especially useful for preventing abrupt closure and/orrestenosis of a blood vessel by the delivery of an antithrombic or othermedication to the region of it which has been opened by PTA. Theinvention permits the release rate of a bioactive material to becarefully controlled over both the short and long terms. Mostimportantly, any degradation of the bioactive material which mightotherwise occur by other polymer coating techniques is avoided.

As noted above, the structure 12 of the medical device 10 of the presentinvention is most preferably configured as a vascular or other stent.The typical dimensions given above for a vascular stent are about 10 to60 mm in length and an expanded diameter of about 2 to 6 mm wheninserted into the vascular system of a patient. It is believed thatthese and other specific disclosures made herein, along with aninspection of the drawing, attention to the disclosure of the specificcommercial examples of suitable stents noted above and the generalknowledge of stents possessed by anyone having even rudimentary skillsin this art, make it abundantly clear that such a vascular stent iscylindrical in shape. Indeed, a tubular or cylindrical, thin-walledshape is characteristic of vascular and other stents; see, for example,U.S. Pat. No. 4,580,568 (Gianturco, Apr. 8, 1986); U.S. Pat. No.4,776,337 (Palmaz, Oct. 11, 1988); U.S. Pat. No. 4,907,336 (Gianturco,Mar. 13, 1990); U.S. Pat. No. 4,733,665 (Palmaz, Mar. 29, 1988); U.S.Pat. No. 4,739,762 (Palmaz, Apr. 26, 1988); U.S. Pat. No. 4,800,882(Gianturco, Jan. 31, 1989); U.S. Pat. No. 5,102,417 (Palmaz, Apr. 7,1992); U.S. Pat. No. 5,282,824 (Gianturco, Feb. 1, 1994); and U.S. Pat.No. 5,632,771 (Boatman et al., May 27, 1997), the entire disclosures ofall of these being expressly incorporated by reference herein.

With particular regard to the embodiments of FIGS. 7 through 10D herein,it has already been noted that FIG. 7 discloses a stent having aplurality of arms shown in a flat or planar state prior to being coiled.Again, in view of the common knowledge in the art, it would appear to beabundantly clear to anyone having even rudimentary skills in this artthat such coiling could only yield a stent having a thin-walled,cylindrical shape. It was further noted above that the walls 28′ may belaser cut, etched or stamped into the base material 14 of the arm of thestent, and that the wells 28′ can be square shaped (FIG. 10B), or can beslots or grooves.

Accordingly, it should be clear that the foregoing disclosure andaccompanying drawing necessarily and inherently disclose furthercharacterizing features of a stent within the scope of the presentinvention, such necessarily disclosed features permitting the stent tobe described in terms of its thin-walled, cylindrical shape.

Thus, in an additional aspect, the present invention can becharacterized as being directed to a stent comprising a generally thinwalled cylinder, the cylinder having or containing a plurality of arms,the arms being expandable and having a generally uniform thickness; andat least one well 28′ formed in at least one of the arms, the well 28′having a closed perimeter on all sides and an open top, and the well 28′being smaller in all dimensions than the arm, the well 28′ containing atherapeutic agent applied therein and wherein the therapeutic agent isan immunosuppressive agent. The wall 28′ can be generally rectangular orsquare in shape. The immunosuppressive agent is preferably cyclosporin.

In a further aspect, the present invention can be characterized as beingdirected to a stent comprising a generally thin walled cylinder, thecylinder having or containing a plurality of arms, the arms beingexpandable dependent on the amount of force applied to the arms, and thearms having a generally uniform thickness; and at least one well 28′formed in at least one of the arms, the well 28′ having a closedperimeter on all sides and an open top, and the well 28′ being smallerin all dimensions than the arm, the well 28′ containing a therapeuticagent applied therein; wherein the well 28′ has a generally rectangularperimeter.

In yet another aspect, the present invention can be characterized asbeing directed, in combination, to a stent comprising a generally thinwalled cylinder, the cylinder having or containing a plurality of arms,the arms being expandable dependent on the amount of force applied tothe arms, and the arms having a generally uniform thickness; and atleast one well 28′ formed in at least one of the arms, the well 28′having a closed perimeter on all sides and an open top, and the well 28′being smaller in all dimensions than the arm, the well 28′ containing atherapeutic agent applied therein; wherein the well 28′ has a generallyrectangular perimeter; and wherein the therapeutic agent is animmunosuppressive agent coated on the well 28′. The well 28′ can belaser cut into the arm. As before, the immuno-suppressive agent ispreferably cyclosporin.

In a still further aspect, the present invention can be characterized asbeing directed to a stent comprising a generally thin walled structurehaving or containing a plurality of arms, the arms expandable to assumethe shape of a lumen into which the stent is emplaced, the arms having athickness, and at least one well 28′ formed in at least one of the arms,the well 28′ having a closed perimeter on all sides and an open top, andthe well 28′ being smaller in all dimensions than the arm, the well 28′containing a therapeutic agent applied therein and wherein thetherapeutic agent is an immunosuppressive agent. Again, theimmunosuppressive agent is preferably cyclosporin.

In another aspect, the present invention can be characterized as beingdirected to a stent comprising a generally thin walled cylinder, thecylinder having or containing a plurality of generally solid arms, thearms being expandable dependent on the amount of force applied to thearms, and at least one well 28′ formed in at least one of the arms, thewell 28′ having a closed perimeter on all sides and an open top, and thewell 28′ being smaller in all dimensions than the arm, the well 28′containing a reservoir of a therapeutic agent applied therein.

In an additional aspect, the present invention can be characterized asbeing directed to an expandable, self-expanding or expanded stentincluding including a base material, wherein at least one well 28′ isformed in the base material of the stent, the at least one well 28′containing a bioactive material applied therein. The bioactive materialcan be an immuno-suppressive agent, an anti-proliferative, anantibiotic, and anti-inflammatory, a growth factor inhibitor or aremodeling inhibitor. The immunosuppressive agent is preferablycyclosporin. The well 28′ can be configured as a groove.

The details of these aspects of the invention have already beendescribed with respect to other embodiments of the present invention,and therefore need not (and for brevity, will not) be repeated.

The other details of the construction or composition of the variouselements of the disclosed embodiment of the present invention are notbelieved to be critical to the achievement of the advantages of thepresent invention, so long as the elements possess the strength orflexibility needed for them to perform as disclosed. The selection ofthese and other details of construction are believed to be well withinthe ability of one of ordinary skills in this area, in view of thepresent disclosure.

Industrial Applicability

The present invention is useful in the performance of vascular surgicalprocedures, and therefore finds applicability in human and veterinarymedicine.

It is to be understood, however, that the above-described device ismerely an illustrative embodiment of the principles of this invention,and that other devices and methods for using them may be devised bythose skilled in the art, without departing from the spirit and scope ofthe invention. It is also to be understood that the invention isdirected to embodiments both comprising and consisting of the disclosedparts. It is contemplated that only part of a device need be coated.Furthermore, different parts of the device can be coated with differentbioactive materials or coating layers. It is also contemplated thatdifferent sides or regions of the same part of a device can be coatedwith different bioactive materials or coating layers.

What is claimed is:
 1. A method for preparing a medical device,comprising: providing a vascular stent comprised of metal and having aplurality of discrete wells located in the metal and a surface betweensaid wells, with each well of the plurality of discrete wells having aperimeter defined by sidewalls extending downwardly from said surface toa bottom wall extending transversely to and terminating at the sidewallsand providing a closed bottom to the well; and depositing a materialcomprising at least one therapeutic agent into wells of said pluralityof wells.
 2. The method of claim 1, also comprising: laser drilling saidwells into said stent.
 3. The method of claim 1, wherein the at leastone therapeutic agent comprises an immunosuppressive agent.
 4. Themethod of claim 1, wherein the at least one therapeutic agent comprisesan antiproliferative agent.
 5. The method of claim 1, also comprisingdepositing a porous polymeric layer over said material.
 6. The method ofclaim 5, wherein the porous polymeric layer comprises a bioabsorbablepolymer.
 7. The method of claim 5, wherein the porous polymeric layercomprises a bioabsorbable polymer selected from the group consisting ofpoly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly (hydroxybutyrate-co-valerate),polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid),poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate),polyphosphoester, polyphosphoester urethane, poly(amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),copoly(ether-esters), polyalkylene oxalates, and polyphosphazenes. 8.The method of claim 7, wherein the bioabsorbable polymer ispoly(L-lactic acid) or poly(D,L-lactic acid).
 9. The method of claim 7,wherein the bioabsorbable polymer is poly(lactide-co-glycolide).
 10. Amethod for preparing a medical device, comprising: providing a vascularstent comprised of a plurality of arms comprised of metal with said armsconverging and meeting at a plurality of bends and having a plurality ofdiscrete wells in the metal of said arms, with each well of theplurality of discrete wells having a perimeter defined by sidewallsextending downwardly from a surface of the stent to a bottom wallextending transversely to and terminating at the sidewalls and providinga closed bottom to the well; and depositing a material comprising atleast one therapeutic agent into wells of said plurality of wells. 11.The method of claim 10, wherein the at least one therapeutic agentcomprises an immunosuppressive agent.
 12. The method of claim 10,wherein the at least one therapeutic agent comprises anantiproliferative agent.